Stroke occurs in 10% of children with sickle cell anemia (SCA) and has a very high risk of recurrence without therapy. Affected children receive chronic erythrocyte transfusions to prevent a secondary stroke, which are effective but have limited long-term utility due to transmission of infectious agents, erythrocyte alloantibody and autoantibody formation, and iron overload. Transfusion acquired iron overload has morbidity and mortality for young patients with SCA and stroke, including chronic organ damage with hepatic fibrosis and cirrhosis, poor growth and development, cardiac arrhythmias, and early sudden death. Deferoxamine (Desferal(r)) chelation therapy is difficult to tolerate and leads to non-compliance an alternative to transfusions for secondary stroke prevention is clearly needed, which also addresses the issue of transfusion acquired iron overload. Hydroxyurea can prevent acute vaso-occlusive events in SCA, but its utility for cerebrovascular disease and specifically for the prevention of secondary stroke in SCA, is not proven. Our pilot data indicate hydroxyurea can prevent stroke recurrence in children with SCA, and after transfusions are discontinued, serial phlebotomy reduces iron burden. We propose a Phase III randomized clinical trial for children with SCA termed Stroke with Transfusions Changing to Hydroxyurea (SWiTCH). We hypothesize that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence and significantly reduce the hepatic iron burden. The primary aim is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload. Additional aims include comparisons of growth and development, frequency of non-stroke neurological and other sickle-related events, and quality of life. The use of hydroxyurea for secondary stroke prevention, coupled with removal of excess iron by phlebotomy, would represent a significant improvement in the management of patients with SCA and stroke. If hydroxyurea has efficacy for prevention of secondary stroke, it may also be beneficial for other children with SCA and cerebrovascular disease including those at risk for primary stroke.